Ishimaru Naozumi, Arakaki Rieko, Yoshida Satoko, Yamada Akiko, Noji Sumihare, Hayashi Yoshio
Department of Oral Molecular Pathology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
J Exp Med. 2008 Nov 24;205(12):2915-27. doi: 10.1084/jem.20080174. Epub 2008 Nov 17.
Although several autoimmune diseases are known to develop in postmenopausal women, the mechanisms by which estrogen deficiency influences autoimmunity remain unclear. Recently, we found that retinoblastoma-associated protein 48 (RbAp48) induces tissue-specific apoptosis in the exocrine glands depending on the level of estrogen deficiency. In this study, we report that transgenic (Tg) expression of RbAp48 resulted in the development of autoimmune exocrinopathy resembling Sjögren's syndrome. CD4(+) T cell-mediated autoimmune lesions were aggravated with age, in association with autoantibody productions. Surprisingly, we obtained evidence that salivary and lacrimal epithelial cells can produce interferon-gamma (IFN-gamma) in addition to interleukin-18, which activates IFN regulatory factor-1 and class II transactivator. Indeed, autoimmune lesions in Rag2(-/-) mice were induced by the adoptive transfer of lymph node T cells from RbAp48-Tg mice. These results indicate a novel immunocompetent role of epithelial cells that can produce IFN-gamma, resulting in loss of local tolerance before developing gender-based autoimmunity.
尽管已知几种自身免疫性疾病会在绝经后女性中发生，但雌激素缺乏影响自身免疫的机制仍不清楚。最近，我们发现视网膜母细胞瘤相关蛋白48（RbAp48）根据雌激素缺乏的程度在外分泌腺中诱导组织特异性凋亡。在本研究中，我们报告RbAp48的转基因（Tg）表达导致了类似于干燥综合征的自身免疫性外分泌病的发生。CD4(+) T细胞介导的自身免疫性病变随着年龄的增长而加重，并伴有自身抗体的产生。令人惊讶的是，我们获得的证据表明，唾液和泪腺上皮细胞除了能产生白细胞介素-18外，还能产生γ干扰素（IFN-γ），后者可激活IFN调节因子-1和II类反式激活因子。事实上，Rag2(-/-)小鼠中的自身免疫性病变是通过转输RbAp48-Tg小鼠的淋巴结T细胞诱导产生的。这些结果表明上皮细胞具有一种新的免疫活性作用，即能够产生IFN-γ，从而在发生基于性别的自身免疫之前导致局部耐受性丧失。
